HUT53097A - Process for producing thiophene derivatives and pharmaceutical compositions comprising same as active ingredient - Google Patents

Abstract

2-Hydroxy-3-thienyloxypropylamino compounds are described as useful in the treatment of obesity and related conditions. Processes for their preparation are described, as are novel intermediates and pharmaceutical compositions containing them.

Description

The present invention relates to a process for the preparation of 2-4hydroxy-5- (cyenyloxy) -propyl-eaino compounds (especially phenoxy-aecyl * esoporphs) and ferrets of terracnose. The mermaid is our ether! eljártakéi

-2productable compounds injected into the bloodstream have a temogenous effect »ancestors induce heat loss in their physician's doctor · this is a good example of delayed companion and similar disorder (such as deleterious obesity in diabetes)» · Petrified european sashadal application announcement heaps suitable for culling obesity · set pathetic · ast pathetic · inventive sserin-producing compounds significantly improve the temperature of this rainfall · and / or other insolvency contributions k * | For example, some people exhibit adverse effects as érrendsserre compounds non · Abnormal by * hlsás and related disorders késelésére elkaInas vegyülatokkel rain my táasestott important követelnésy s * _t that upon orders with no sselektiv region itself · from the ASE "point of this invention sserint obtainable compounds hatásprafilja extremely popular rain ·

The present invention provides pharmaceutically acceptable salts of the compounds of formula (I) sserine and the general formula: wherein λ is an oxygen atom bonded to a compound of formula (I), and a hydrogen atom is bonded to a single propoxy side chain bonded to the ortho bond. or fluorine

R * denotes xrboxyl · (1 * 6 cyanoalkenoxyalkyl) carbonyl * - · 1-6 snenonone Icenoyl or * (cH ₂ ) _fi 0K ^, and in the latter formulas

R ² hydrogen ethane · optionally hydroxyl · 1 * 4 Ionic ♦ · «• 5.

alkoxy · »phenoxy ·» carbonyl! * »(1-6 falling alkyls) * • carboxylic acid, dl · (1 * 6 essential esters of Lkil) * carbaoyl ·, pyridyl ·» fsnyl- »chloro-fanilyl 1-6 carbon atoms substituted with a chloropyridyl group or a 3-6 alkenyl moiety alkylene moiety »3-6 alkenyl moieties 3-6 heteroatoms or a halogenated * gene ·» 1-4 xenetic acid moiety » -4 salts of alkoxy * · trifluoromethyl- »cyano * or nitro-esubstituents denote a thienyl group * and at the time of the transaction hydrogenated» 1-6 alkenyl or -OS ⁴ alpha-haloeno group »and the latter formula * bon l ⁴ denotes hydrogen ether »1-6 carbon monoxide optionally substituted with hydroxy * or 1 * 4 carbon monoxide moieties» optionally substituted with hydroxy or 1 * 4 alkoxy alkoxyl groups> 6-alkenoylphenyl-phenylethoxy-3-phenylethynyl l * 4 carbon tonne alkyl) • a group or non-til * (alkyl of 1- * carbon) * • a group »or

R ² and 2? together form a 4 * 7-membered poliaatilés Lang * wherein optionally one aetiléncsöpört site as appropriate as -KR ^{2 »5} group nitrogénétokjától ásónstoanal alválaastva least two oxygen or S * · lehat» as sending e-poliaatilén two gages ssoaasédoo ssénstonja optionally 4-7 member polyOBtilene blob! may be bonded to a benzoyl ring and the latter may optionally be halogen · »1 * 4 carbonyl alkyl *» 1-4 carbonyl alkoxy * »trinino-oatyl ·» cyano * or nitro-azo-astitic »or • ♦ Κ ² and i ⁴ together can make 3 · * tegn polyia & Éo chains,

S? hydrogen®toao, 1 to 4 moleo planes means 1 le sweeping lake or 1 to 4 aseneetomo alkanols, and n is · 1, 5, or 5 · in a compound pump of general formula (X) · os -OCHgR ¹ ssubeatitueas ordinary ®r int a thienyl-oxy-propyl-aninoethyl-chemical is linked to the thienyl-oxy-propyl-anino-ethosylchloride by linking it to its node or site (target site *).

The compounds of general formula (X) or else myosinopropoxy solubles have a thiophene ring which can be fused at $ * ss. The 2-lenyl-compounds may be substituted for js in tbc · in the case-case chlorine or fluoro at ss ^ sstit, or until the 3-thienyl-compound in the 2-position or 4-position of the given ether is a chloro or fluoro substituent may be attached · submissive and compounds of formula X · in which the thiophene-guurryl is non-attached with additional ssubastitaono;

Depending on the meaning of the compounds of the general formula (1), they may be enino-atoxy-Xanyl-isomers (X is an ozogenone) or aninoethyl-phenyl-esters (X is a valence bond).

One class as the compounds of formula (X) in the rain ssámesékok constitute · probabilities does -co® ¹ h ² · t ^ group elderly compound pumpkin · S ² such as H »1-6 szénatonos alkilcseportot (e.g. methyl ·« 611-, isopropyl-a-propyl-butyl-pentyl or hesilea) or 3- to 6-membered alkenyl moieties (such as allyl moieties). As an R ² substituent, 1-6 sennatono alkyl or > 6 osenotonoe elkenll as an example of a mubs substituent! bidroxllceoport · • · · k

- 5 1-4 szénatoaoa slkoxiaaopert (such as methoxy or etoxicscport) fonllG _{9 »9} Opor karbaaoilesőport ₉ (1-6 szénatoaos slklD-ksrb» trimethylhexanoyl ceoport (e.g. »^ karbaaoil-methyl group) ₉ di (6 osénabemos alkyl) -carboxoyl (such as dimethyl-xrbanol group) or pyridine-isopropyl

R ^{2 for example} 5-6 carbonaceous slkini 1c may be substituted for propynyl.

K ² 5-6 Cyclo-ethylcyclopentene with a 6-benzene content This allows for the release of cyclopropyl, cyclabutyl, cloplopentyl or cyclobexyl ·

R ² is optionally aa consisting renilcsoporthon eeetbon halo-substituted exemplary bróa- ₉ chlorine or fluerato · * »1 * 4-esénatonoa slkll szubestituensként e.g. aat 11 * or ethyl» 1 * 4-asónetoaoe elkoxi esuboatitatásként exemplary wound or otoxioooport oxl- * ₉ in addition trif luor-oe tll * ₉ oll * or nltro-substituent may be attached ·

R 1 * © 6 eeénatoaee tiki1csöpörtként example ethyl, or represent etilcaoportet · «* or ditaUtóos compares mean formula of this group · aa body (1) compounds of formula hldroxáneav-Sbarra * aaékoknak can I · R ₉ are preferably optionally substituted by hydroxy hidrogénétoaot or 1 to 4 carbon atoms of the alkoxylated alkyl group (such as ethyl * ₉ ethyl * »propyl- ₉ butyl- ₉ 2 * hydroxyethyl- ₉ 3-hydroxypropyl * ₉ 2 -ebaziethyl) customized by lkoxic - or 2 * ethyloxyethyl) ₉ may be optionally substituted with 3 to 6 aromatic alkenyl groups (such as the yl group) or 3-6 carboxylic acid substituents (such as propyl group) optionally substituted with a hydrocarbyl group or a 1 to 4 alkylene alkoxy group; preferably it may be hydrogen or 1-6 carbon atoms alkyl;

R ² and $ together form 4-7 tegn polymethylene residues - 6 hot * assists R ² and R ^{3 can form} a bonded nitrogen »together 1> 8 tegu heterocyclic group · Optional oxygen atom on one of the polyethylene chains on the otylene group The group As may be, for example, pyrrolidino-piperidino, hexahydro-esopino-norfolino or thiamorpholino. Any of the two "soy-soluble" fatty oils of the polyethylene chain may optionally be part of a benzene ring condensed with this polysstylene chain. The halogen atom may be exemplified as an optionally osebestitone of the bonsole ring (thus leaving a "fluoro" or "breton") *

1-4 carbon monoxide alkoxy groups (such as methyl * ethyl or propyl) * 1-4 carbon monoxide deactivated (so no cosine or ethexiosopork) * trifluoromethyl eeoport * cisnocarboxy or nitro group attached

The compounds of formula (I) which are long-lasting compounds of this group have the following properties: the H ² and R * combination together form a 5-membered polymethylene chain * the R ² and R * together with the nitrogen and oxygen moieties of the covalent bond. or a tetrahydro-isooxazoline group * and a further group of compounds of formula (I) and fatty acids * in which R ^{1 represents a} carboxyl group or (1-6 alkenoxy-alkoxy) -carbonate 1-ceoporto · R ^{1 is} preferably carboxyl - * methoxyterbonyl, ethoxycarbonyl * n-propoxyterbonyl or torso-becoxytteronyl group lobes ·

As (1) a compound of formula tek ejobb ooopartját constitute the rain ssársssékok * probabilities ^R1 1-6 aiénstosoa elkanoilceoportot * * such as formyl, acetyl or propionl 1csöpörtök means.

A further group of compounds of formula (X) and derivatives may be represented by the formula: R * - (cBg) gO ^ - wherein n is 1 * 5 or 5 »Big hydrogen ethers * 1-4 precursors of thorazoloyl (Thus oootil »or propionilesöpörtót) or 1 * 4 szénékoros slkilesoportot (Thus rotil» * * st · propyl or butyl «© port) · s · As such a signal (X) falls to the formula R ^l lap pouch as ethoxycarbonyl group may monoethyl ·

The olefinic group of the compound of formula (I) is represented by the compounds of the formula β (Π) - in which the oxygen atoms represent a bond and the R ⁶ is xrboxyl * (C 1-6 -alkoxy) carbonyl * fcerbaeoll- »( 1-6 eaen-thromoalkyl) -carbberol- * hydroxy- (1-6 carbon atoms ald-korbSBoyl) * (1-4theneoxy-alkoxy) * (1-6thene-heteroarylalkyl) -oxybenzoyl * di- (1-6thene) torosalkyl) -carbenol *, piperldlnov or Borfolinoasopart ·

Particularly preferred compounds of formula (II) are the derivatives of formula (HA) wherein X is oxygen and the eninopropoxy side chain is attached to the 5 position of the thiaphene ring.

In the compounds of the formulas (Π) and (HA), R ^{6 is} particularly preferably selected from the group consisting of kerboxyl, ethoxyceronyl-carbonyl-baryloyl-rotyl-xrbsBoyl and (2-aetaxyethyl) -carbenoyl.

Básiknrok Ai (X) Compounds of formula * naak Begfelelűen pharmaceutically tilsg eltolnazható acids may form ssvsddioiós salts · Some compounds of formula (I) (e.g., R ^L is karboxilesöpörtök tortalnssó ssármzékok) formed asfoterek * such itorlonos fmáben * and pharmaceutically altolneshstó acids and Pharmaceutically * · pushing shs lake cation serving bases 1 can form salts · pharmaceutically acceptable salts of the compounds of formula (X) with an example of unsaturated acids * • 8 · sett Bók * i ^ y hilrogen halides (first) hydrobronides) * asphaltates and foams * salts with eservoe rows, such as vaccines * citrates * lactates * tartrates and oxolates * and addition salts with soluble polarears. Salts formed with bases which have a physiologically acceptable cation supply include alkaline * · * and alkaline * salts such as potassium, soda, sodium and isotonic salts, as well as salt and salt. neg · as (1) contains one or more asxinnetrikuean ssobastlated sequences * correspondingly can be formed in optically active onantloaezes and optically inactive reenates · We need to provide compounds of formula (I) / rogy (two rounds for compounds containing aaslasotrlosontrar) includes the ability to produce dUsstoteoisonone passageways * when administered to our nephews, induces a tersogenic back * As individual isosers for ions in salt · e.g. Examples of the teraogenic effects of the compounds are discussed later with ianer · sweeteners. and the preferred compounds of formula (X) are optically active isoforms (asss a / · / tear fractions * aai cahn * Ingold * Prelog renderer eserlnt as AZ-cone-bonded ions are responsible for Mg) · our assumptions are based on the R ¹ bolyene carboxyl group different esnbostituenat * primarily (1 «6 ssénatoeos elkoxO carbonyl group falls tar -COISI ² ^ group of the formula * tslrosó (I) compounds of the knives nelegvérüek eserrosetében transforming least REASON the segfelalő * R ^l bolyok carboxyl tartalrosó formula (1) Formulated Salt »* - · · * 5 * Shakes are very significant and have a very selective temogenic effect · the compound is · ^ * · * unleaded as a living merve setbo can become yak later la * to be healed in the girls' tournament, or * preferably * in the live morvarnt, it is formed directly by the formula of sedge (I) from hating leaks.

The general formula (I)! compounds are exemplified o the following are plated

4- £ 7 »(2« hydroxy - ^ - /> »thyloxy-oxyl-propyl-eaino)» etij7 * ü? <No * i · • oce tsa vm »til-ester, áo ^ JT · (2- hydroxy N · [5-tenyloxy / (propyl enino) -ethoxy] -7-phenoxy • eco-acid * methyl ester · (3) · * »(2 · 1 · 1 · droxy * 5 - />» thienyl) xxi / -propyl-a »ix») -et ΐχ7 · Γen · oxi-eee tssfHMtil ~ jaster ₉ (3) · 4 - /)? - (2 · ϊιί0Γοχ1 · 3- / 0 · Ιenen-oxi / -pw > pil-anino) * e toxj ^ phenoxy ~ eco tm> * not tH-esto? ·

4 «^ * (2 ~ bidroM ~> ^> - Meni] ^ xÍ / * prQpil ~ OBlno) * otaxA7Ufenoxi * • acetic acid,

4- £ 5 »{2» hydroxy -> - / 5 * thien il-oxyl / -propyl 1-esino) «e ty /« * phonexi · • oeotmvt (he) -4 «^» (2 »hydroxy *> V5 * thienyl ^ 9xi / «^ ropil ^ Bíiw) -otoj ^ 7 * ton · oxi« oeotsav ₉ ((2-hi hydroxy-J - /> - t le ni 1-οχ1 / · ρτορ! 1- «Β1ηο). -o ^ tl ~ 7 foi> »oxíoocetsav, lw (2-aefcoxi-ethyl) -4 - ^? - (2-droxl hi-5 - /> thienyl-oxy / -propyl to qualify) -e toxl7- ^f enoxi-oeeto mid,

B- «e til * 4w ^ M2 ~ hydroxy -> - / 3-t lentiem i / -propll-aBino) -e tox | 7 ~ -phenoxy-eeote nid, 4« ^ · (2 · 1ύ.ύΓθχ1 ·> * / 3 · Ι1οη11 · οχ1 / · ρ £ ^> ορί1 «βΒ1ηο) · βΙοχΧΓ '> £ βηοχ1 · -acetanides ₉ • lu (o) -4- £? - (2-hÍdlOXÍ ->» / 5-tÍenÍl-OXM -pXiOpyl-8 (amino) -eth0347-phenoxyl-ethoxy add · S-ethyl-4- [7- (2-hydroxy-5- (trans) thienyl-oxy] propyl enino) -ethyl] -phenoxy aoeid · de (ü) «Kmm ί 11-4 - / - (2-ηΐ0ΐοχ 1-5 - /> · Ι-phenenyloxy / -propyl-8oino) -ethazo-phenoxyacetenide · The invention further relates to aa ( 1) a compound of formula (1) or a pharmaceutically acceptable salt thereof for the preparation of a salt for a medicine. In addition to this roofing material, this roofing material also has a variety of medical remedies for snow »dosos» »thinners * and / or other excipients for topics ·

The pharmaceutical késsitnényok konpoaiciók e.g., oral or parenteral administration, such as tablets, pills ₉ tepaaslák · · _t Vise powders or solutions or they may be oily solutions and sterile injectable siusspensiók eaulsiók Vise vsgy ssusspensiók · _t or oils of

Oral Healing Seraphomas Are Beneficial To Therapies

Medicinal mushrooms can be prepared with the usual herbal remedies for herbal medicine using isanal medicine technology. for example, a tablet of rogy kepasule rendaserin may contain, for example, 0.1-250 ng of the active ingredient. & &quot; Remedies for treating oesophageal and other disorders commonly used to treat abnormal substances other than compounds of formula such as appetite lubricants · vitenins and hypoglycemic agents.

and orally administered medicinal delays • ·

- 11 representatives of 6 sustained release or delayed-release formulations * such as tablets containing the insoluble or bulky polymer filler or coated foot * Dosage of * these * formulations in the unchanged form * felsssbadulnak the késeiteÍnyből * tas jd into the bloodstream · EEE purpose effect by the compound of formula I or rains gyógyássatilag slkelMshstó salt as (I) rendsserint daily O _t 002-20 sg / kg dosis * preferably day 0 * 02 * 10 mg / kg DOS ieban inject air into our blood * dressings enberakns · «st s take weekly quantities of one dose per dose can be delivered to sserveeet · but oeakonbor is obvious * that s treates necessary dysplasticity depends on the severity and age of the taseleodo disorder o above may differ from the stated values ·

The compounds of formula (I) further reduce the triglyceride and colossterine levels in the blood and increase the four-density lipoprotein levels in the blood * and, preferably, they can be used to delay the disease or disorder * where s is used to reduce (or increase) · ssűkség such as compounds of formula (I) as hipertrlgliceridénie hiperkolessterolénia * e »of the four low-density lipoprotoin konoenbr Tax related disease states as érelnesseaedés velanint * (* thus koseomér-« child and peripheral atherosclerosis) and _t sslv- áxrondsserl disorders and similar abnormal conditions alkelnsssk ·

For the listed medical purposes, compounds of the general formula (I) or pharmaceutically acceptable salts thereof * · ·

- 12 ® used to blur tops of flax in the form of medical knives · In the case of medical knives and other disorders such as ficcates, besaflbrates and gioflibestes; for example H 2 G-CoA reductive inhibitors (such as lowsststin »asiaveestetin and prevestinin)» »millet» * anti-terlxbsorption agents such as B-sithosterol and colxterl-acyl-transfusion inhibitors cross-linked dextran dialkyl &lt; RTI ID = 0.0 &gt; &lt; / RTI &gt; nicotinic acid, alkotinic acid, nicotinic acid salts, IMtitemin, and thyrolyte active ingredients.

The compound case of formula (2) and the healing salts of acorns ® according to the invention can be obtained by using the following 6 methods.

a) Compounds of formula (III) · In formula *, x and R ° can be reacted with compounds of formula (I ¥) above - wherein R * is as defined above and

L stands for leaving group * | obsession

b) the compound of formula (V) * in the formula * R® is · re-reacted with the compounds of formula (VI) above · X and H * are the above * | obsession

c) Compound of Formula VII · in two * »formulas X» S® and fi * have the same meanings as set forth above. obsession

d) The compound of formula (I) containing R * in kerbsmollc sweeps to produce compounds of formula * lánoe & &lt; RTI ID = 0.0 &gt; VIII &lt; / RTI &gt; And then, if desired, converting the resulting compounds of formula (I) into a compound of formula (I) * and / or the compounds of formula (II) ss (I) are converted to their pharmaceutically acceptable salts *

As the L-escaping L-esparte in the compounds of Formula IV, for example, it may be: N-toluenesulfonyloxy-p-toluenesulfonyloxy or chlorine, iodine or bromine. · Reaction of compounds of Formula (HI) and (IV) usually bait »such as inorganic bale * such as alkali metal carbonate or acetic acid (e.g. potassium carbonate or sodium acetate) in the presence of a mixture of potassium hydride (e.g. sodium hydride) at temperatures ranging from 10 ° C to 12 ° C, usually ssoba temperature * a suitable solvent or dilution may be added * such as vinegar * natyl ethyl ketone * prcpao-2-ol * 1,2-disethoxyethane or tert-butyl methyl ether * In order to clamp the renal resin to the nininu * * előssör to (III) with phenols of formula corresponding bésiasal * may react such as potassium t-butoxide, and then formed so as salts and reagáltafejük UCHg-R ¹ formula alkilos sserokksl.

The compounds of formula (III) may be prepared by ionic sulfuric serum serines. For example, the phenol of formula (IX) wherein X is as defined above may be prepared in the presence of a suitable solvent such as an alcohol such as ethanol or propen-2-ol. (V) epősidőkkel formula reagáltafejük · the reaction is usually finite temperature e.g. 1O4LO ° C * the reaction be at the boiling point or ehhős proximal temperatures * As (V) epexidek Taner compounds Guropean knock · Chem ·] £ _v 151/1985 /) * or as may be used to prepare epoxides of general formula As (V), for example, in the presence of a thiophene-holpgeaid (such as thiophene-bromide) in the presence of an oxide of a protected glycerol (e.g. glycerol-sceton ketal) with the sodium salt * of the resulting residue tat p-toluene lfonátt®! and then the resulting - (tosyloxy) -2-hydroxypropoxy-tIgphene is basically delayed * In the above reaction, the glycerol-acetone-substituted compound can be digested in the form of the optically active compound racoate.

The compounds of formula (V) and (VI) are usually reacted with one another under the conditions described for the reaction of compounds of formula (V) and (XX) * When a compound of formula (VI) containing an alkoxycarbonyl group is used instead, The compound of formula (VI) may also be self-condensed or may undergo a polymerization reaction. Because of the unfavorable nature of the competing anticancer agents, the compounds of formula (I) in which R ¹ is substituted for sicoxylcarbonylceoport are preferably prepared by the Ms method. * The starting materials of formula (vi) can be prepared by Under the conditions described for the reaction of compounds of formulas (III) and (IV) with compounds of general formula (IV):

For the reduction of the compounds of formula (VII), for example, boron anhydrides or cyanoborohydrides may be cleaved in the presence of a suitable polar solvent, such as a netanol in ethanol, the λ reaction does not require extreme temperatures.

In the preparation of starting materials of formula (VII), compounds of formula (x), wherein H 0 is as defined above, are reacted with compounds of formula (XI), wherein x and R ¹ are as defined above.

does not require extreme temperature · «reaction usually in inert solvent» such as polar aprotic solvent · such as scatonitrile · proceeds to react chemistries of formula (VII) with their alkaline reaction mixtures * ·

Compounds of formula (X) can be prepared by reacting compounds of formula (0) with agony. Usually, the salt is admixed with a solution of cetyl alcohol * In the preparation of compounds of formula (UD), compounds of formula (aII) ( Reaction with a compound of Formula XV: The reaction was carried out under standard conditions when reacting a compound of formula (XVII) with a compound of formula (XV).

The hydrolysis of the compounds of formula (VIII) is usually carried out under the usual conditions for the nitrilization of fluids. Hldrolisisb under mildly alkaline conditions may be carried out in the presence of, for example, alkali metal hydroxide, such as sodium hydroxide. The compounds of formula (VIII) may be similarly prepared as described above for the preparation of compounds of formula (I), e.g. Compounds of formula (II) are reacted with compounds of formula (r-CHg-CN) - wherein L is unsubstituted.

For example, the compounds of formula (1) are converted to other compounds of formula (1) as follows:

Reaction of the compound beetle (X-6) containing (1-6 acenoxyalkoxy) carbonyl group with As 1Λ is carried out by reacting chemical compounds of formula (X) · The reaction is rendssarine in an inert solvent such as 1-4 carbonated alkanol (e.g. or etenol) at a moderate temperature (e.g. 0-60 ° C). If volatile omines are used, the reaction may be carried out at a pressure higher than atmospheric. Λ ^ MKH ² reagent is usually used in excess. preferably starting from a compound of the general formula (X) in which it has ¹ methoxycarbonyl or ethoxylcarbonyl group. It can be obtained by converting a tetroxyl group converted into a &lt; RTI ID = 0.0 &gt; carbonyl &lt; / RTI &gt; The compounds of Formula I are appropriately protected with salts of the fatty acids by reacting with compounds of the general formula: - The reaction may be carried out under known conditions of the aeroil. Usually carried out in the presence of a caposol ester ₉ such as dicyclohexylcarbodyldil · Before the reaction is completed, a blood group is applied to the sensitive leading sports of the compounds of formula (I) | the hldroxilcs © port védhstjük example ssllilezéssel · «protecting groups of as © cllesé after © táw11thetjük by known sódaserekkel · can be converted to it (1) carboxylic acids of the formula comprise a suitable esters similarly · Assista ^R1 bolyok (1 * 6 szénatoaoe 1 kox 1) carbonyl ! 1-group derivatives.

and compounds of formula (I) wherein R ¹ is a xrbexyl group can also be prepared with the corresponding esters of formula (I) or amide (e.g., by hydrolysis of an alkaline or enzyme). The hydrolysis may be carried out under conventional conditions.

As the base for 17 * hydrolyzate; for example lltiuse · »sodium potassium hydroxide potassium hydroxide can be used · the reaction is usually carried out in a suitable solvent or diluent» such as water in a 1-4C alkali salt · usually at 1 ° C to 110 ° C · in the presence of groups tart® foo salt (1) compounds of formula ételekithetjük hőböntéssel also the corresponding (X) with a carboxylic acid of formula KKA »the heat bon normally ry t-10u 220®C C _f is optionally carried out hlgítószer, IGJ diphenyl ether in the presence · .'Z s? where -h ^4, hydrogen is substituted tantalum, the compounds of formula (I) can be prepared by: o coupling a corresponding compound of formula (I), wherein or reacted with reagents erileaő · digs O elkilósáét usually about 1 equivalent charm sis presence végeseük · hydrogen as & 1nasé holder (1) compounds of the formula under the same conditions ü * _t S dialkileshet Juk | the reaction employs about 2 equivalents of the bale · the salts of the compounds of formula (1) · have the potential to form a ^{2 to 4} membered poly (ethylene) chain · or alternatively may be prepared by substituting a halo group ( 1) compounds of formula χΛ- (0Η ₂₎ * «·. / general képlotü vegyülőtsk-

2 - m is 5 compounds 4 _t and X> and b are compounds of formula (X) are prepared by reacting a compound of formula (1) in a known manner with a corresponding compound of formula (X); With "bases" 11 with bases · In the case of the preparation of hydrogen halides 18.

we can go u- .. _; also »that the hormone ball is subjected to thischiometric amount of hydrogen in the presence of 1-halide in the presence of 1-halide, the following salt was refluxed for the next sake to increase their heat capacity for 4 days 4 ®G was converted * then the animals were kept in a 23 ° space for 2 days · then the next test was administered subcutaneously or orally to this test compound · After 1 hour, the animals were sacrificed 1 * and these animals were removed, shoulder blades stone her body fat tissue · from centrifugal ligation of the removed corpus luteum we made a nitro-caudium preporate proton · and by using the method of Üollowey et al. We chose · «when it was animals only uo and a Comparative Study was performed when animals were dosed with 1 mg / kg isoprenaline in the form of its sulfate. The test compounds were usually administered at doses of 1 »o * 3 * l * µ * 3 * 0 and le mg / kg * and were expressed as linear regression-enel isiesel SD ^^ relative to the GDiMzeg binding induced by lsopre malime. * vasculature (dose required to reach 50 'ss with effect of ss isoPre na 1) We copied · Compounds A were considered to be dancing · if in this experiment the amount of captured GDP increased significantly ((b) ) Rats were kept for 2 weeks in a 29% (teraonautric) environment in order to reduce the number of animals that were * mediated by the animal. · ························································· ·

- 19 · no® floor hŐteraalöképeeségét · «s struggle last day's chin * dewlap hssaásaokUttuk ahhos _t fatgy teabükkös salvdreírrenoiát Sero kapcsomat apparatus (as animal r jgsitettünk lüöáhöi electrode _and the electrode as it is run into IrTran kvenc gallate ess iwpcsoltuk n regttatráló MG lategrátorkos ) · The stubborn ve * collected stake ss (a) reassessmentThe nugha companion was given t ^ 5 $ orally by subcutaneous dosiabon or by subcutaneous » ₉ and 15-30. after the time »gbatarost animals asivfrequency * ^ aatún dőslst íokji« toeen increasing this maturity aisis * 'till the animals s ski vf re kW song reached wgy still downloaded the minute ·%> ο · es arc ye needle out to get the per minute esewerée * alai burnt dos * siat (í ^ qq) · -ϊ so quotient value and s (a) bellygate »gin fellow t value was considered selectivity index (dl) * e sae le kti controversy index about ed The effect of the compounds on the salivary veins is significantly stronger than those of the vasculature of the heart &apos; s &apos; s &quot; Significantly, &quot; rainbow compounds &rsquo; were &quot; significantly &quot; with a + smlctivity index greater than 1 · 1 non-selective effect in the case of isoprenaline, this sscl ^ activity index is 0 »ö6) · (c) ^ bk & nd to increase heat capacity 4 at days at 4 ° -o ^ · deviate car as animals for 2 days at 25 ° Co® térbeu urtot & uk ₉ suyd követkeső the day as -rundel xvuketáróéi and (ii _{Λ ρρί} · · · ^ rhyelol aspixst vnviron · · · áxercise ibysiol 1591-1593 / 1904 /) described in the abdomen of the abusive consuming equipment described above, mg mg stored in the animal metabolism aebe & aegens · after animals * pouch for oral or ssubkutan use about 10 mg / kg. r ··. ··. ···· ·· ··· ... (

·. · ... · .. ·:

• 20 - 0.4 µg / vol% of sodium chloride solution was injected, 25 volumes / volume of Polytorbete ointment vbg} in the aspiration tree was administered. after at least one hour, the rate of »s snyagcm * re was measured. · more © vinagáletbsn these compounds were considered to be effective chances relative to the control. Significantly increased the s rate of change (in the tudent-l'ele t test p 0 _t >). Kohtroll _VISS-b · pets of finite actions were treated bordozóeryeggél · alleles. t \ NTI tested pumpkin sa Altera (1) wherein n Ionic reo.szerint kővetkeső dósisokbea exhibit prince toxieitáere effect without causing symptoms of Juu ^XlMtílet-1 ^ ^tee 50 *? ^Q ' ^{) l} ®g / hg |

-I> 5 te) test 2 ®1 Qg x min ** x body weight increase in kg · · ^ following the administration of 1 mg / kg oral demi ·

ss 1 · plds activity profile of the compound produced by sserin in these above assays (kcv (late). —50 ^sc · mg / kg | ® ^Ce > ²⁰ «« <* «· ^SI cc»> * °° * TopMOfMIL * 5.2 ni 0 ₂ x min * ¹ x body weight kg ⁰ · ⁷⁵ -value increase after oral administration of 1 mg / kg-oc.

The invention is described without limiting the scope of the invention and the following examples are described in detail, unless otherwise stated, (1) the spectra of which are taken at a frequency of 20 [mu] m, using a mixture of L2 ^: -d2 and GD1CX1, chemical shifts are reported as internal tetrsm ^ tylsilyl standard in vanstxostetv * ppm, delta scale | ·· · «·« * 21 - (11) β crystalline terrains for less · 1 data1 neglected • expected aserselves · (lil) lffteetegrefheses solid material spaces Kiaaelgol Art · 7734 type we used to make an espalelter · (manufactured by j. Spaces) company, Crushed, late Federal Co) () (arc) acidification of solutions with wet Indicator Papers (wet) (v) evaporation at reduced pressure, rotary evaporator finite · (vi) melting point values Btehl , Correction Clan Data ·

EXAMPLE 1 τ> ΊΜΗΜ »ΗΓ» ΗίΗ {Η »g 4 - ^ - (2-liloxyl -> - /> - tl * niÍ ~ oxi / -prcpil ~«> altK>) - etty «£ aiiol yu> 1 Hmtoxl> «taanh 1 ol cates are added c,» g potassium »tert-outO, and the © Case is stirred for 10 portions · mixed 0.7 g of broncho-ocoteav-aeU is added, and stirring is continued for more than 16 hours. The olive cereal was flaked and the resulting 2.2 g of a solid was coprecubated on do g ϊ £ 0 for glycol gel. · 6 volumes of our lyophilisate · are sucked with tarfcel © doulos · · /> g of oily substance, aralkalized on standing · · sk is dissolved in 56 liters of dichloromethane, and the solutions are etem niaro ^ ene chloride The solution is acidified to a milk value, the solvent is evaporated, and the crop is evaporated

They were recrystallized from 120 al G «? Til- & cstat and 2o al ^

0.52 g of 4 - [(2-hydroxy-5 - [(2-hydroxyphenyl) -propyl-αBino] -thio] -phenyl-eco-ethyl] -ethyl ether (m.p. 161-163 °) is obtained. t.

*> · * 22 - liMii spectxua voaelaii 2.37-3.03 (a, 2H. 3.0>

-3.26 (a, 41, 3.72 (·, 3K, GH ^)) 3.95-4.05 (a, 2H,

Λ (CBuM), 4.22 (a, Di, t £ CM), 4.74 (a, 2H, OC OC gCO), 6.56 (a, U, lig), 6.74 (a, III). , U ₄ theail), 6.05-7.25 (a, 4ii, ^ ₆ H ₄ ), 7.3b (a. Mi, «5 thiaail) ·

... drop in the image of the eaaaaitotts Gi 53 »ö Off 6.0 Mi 3.5 s» tii 6.6 found 'i Ui 53 »6 2, Mi 6.0 il, Cl 3.5 £» Cli 6 »6 ·

The starting material is set out in the stone stepping stone

1.0 g of 3 * thienylglyloidyl ether, 2, u g of thiophene and 30 &lt; 1 &gt; propan-2-ol were treated with a stream of water for 2 hours. a a ο Evaporate the time series and reflux the residue for 30 g K6 ssilik & gel gel. > Asparagus-growing flies (lu-12 volume o) on Dmolt containing salt of atanol 1 41 chloroacetane were inoculated. 1.3 g of an oily substance are obtained, which crystallizes from the residue 4- [beta] - (2-hydroxy-3- / 3-ynyl * oxo l -pr 0 p 11 -o ino). IjT-phen ol ·

111, spectral lines 2.30-2.98 (a, 2H,

3.00 * 3.50 (a, 4i, o ^ MSC ^) »3» 92-4 »05 (a, 2H, OC3jgCHOH)» 4.22 (a, In, 0 ^.), 6.53 (a, Mi, Uenil), 6.73 (a, 1Μ → 1¼ thienyl), 6.70-7.10 (a, 4B, C ₆ a ₄ ), 7.35 U. 1K, H 1 thianyl). negepahtraai Cl (RH ^) 294 (iua) *

Example 2

-f BiWl-Wtm-mnziHViS '. tium taw

A solution of 1.27 g of 4 * 4? - (2-hydroxy-3- (5-thio-1'-cyano-4-propylaloyl) -ethoxy] -T-xenol in 0.6 g of potassium? tíUtoxlmt; and stirring was continued for 10 minutes. Aa mixed ether (0.65 g) was added.

J

- 25 and ® stirring continued for 16 h of the air, flushed through dletola earth with eluting with methanol · a portion of the thousands of anhydrous material removed · * z shovel * and worn 2 * 5 g For purification, 75 volumes of ethyl acetate gel on K6 are "rosette" columns, 8 volumes per cluster series. Methanol Container Contains Atmospheric Methane. The resulting 1 * 4 > colorless material was dissolved in dichloromethane * and the solution was adjusted to pH * 5 with ethereal hydrogen chloride solution, and the solvent was stored with Ju * and 20 ml of acetic acid and 1> © elite of jítanoL; from the womb Crystal is Yuk. 0 * 3 g of 4-tert-chloro-time of 4- [4- (2-nidoxyloxy) propenyl] ethoxy] -7-phenoxyacea tea v-ae 611 xo púnk | m.p. 156-158 °.

KMd Opactrua Lines 5 * 12-5 · 59 (· ♦ 2íi * CM.W | g ^ H) *

5.45 (6 * 2H * áöQ ^ UÍ ^ O * 5 »75 (» * 5H * GM ₅ ), 5 * 95-4 »10 (a * 2H * UÚ ^ goodUi) * • '4 * 22-4 * 50 '(a * 5Í1 * Ggtitab and IkiCügC ^ Ű) * 4 * 68 (a * 2ii * ui.-dgC'-) * 6 * 55 (® * Id * dg thienyl) * 6 * 79 (a # Ili * thioml) * 6 * 85— -7 * 0 (a * 4íi * Cgii ^) * 7 * 56 (a * Ili * thienyl) · Cloning with C ^ gH ^ XiOgd.liCl base Jani ssáaitotti ui> 1 * 7 * · Bi y * 8> * di 5 * 4 *, ₉ 7 * 7 ^ * l1i 0 * 5, 4 found »Cl 51 * 7% - ₉ Hi 50 £» «1 5,1 ♦ dl 7» 7 £ ·. »CU 8 * 5.

the starting material is prepared as a starting material

2 x 0 g of 5-thienylglycidyl ether * 2 x 9 g of 4-propan-2-ol-4-yl-propan-2-ol were refluxed for 2 hours. and the solvent is triturated * and 5 * 0 g of the residue is chromatographed on 75 g of '-6c oil-gel for thia-tabab · methanol containing increasing amounts (<-12 vol) of methanol as the leaching agent; chloromethane flies are used as solids 2 * 6 8 4 -? - (2-Hydroxy-5- (5-thienyloxy) -propylamino) -ethoxy-7-phenol as a gate at 158-140 ° C.

I w 24 - spectral lines 3 »05-3» 55 (4d * 2H * CHOHG ^ j * 3 * 40 (t * 28, MiC ^ wIigO), 3 * 98 (d * 2H * Og ^ UOH) * 4 * 15-4 * 55 (· * 3H, C&OH and ^ Χ ₆ Η ₄ ), 6 * 56 (* 1H, 1¾ t below), 6 * 60-6.88 (n, µm, C _{6 4 4} and ü ₄ thianyl) »7 * 4; (*, Ul, thienyl) · luminosity spectrum -i-PhaB 510 U + ú) ⁺

EXAMPLE 5 Judgment = Z2dtoolylUl = 2 = Za = ^^ .tuawéM

1 * 37 g of 4- (3-T- (2-Hydroxy-5- [2-ethyl-ethyl] -propyl-enino) -ethyl] -feuol and 100 nl of Tusi are starchy 0 * 55 g ical tert-butoxide was added and stirred for 1 minute. 65 g of bromo-o-cis-ethyl-ethyl ester * are added and the mixture is stirred for 16 hours · the mixture is filtered through diatomaceous earth and the filtrate is washed with a little methanol. 2 * 2 g bsrna oily material for purification are chromatographed on 70 g silica gel silica gel, eluting with 8 volumes of dichloromethane, and the product is dissolved in 00 µl of dichloromethane * and the ethers of the solution are made up to pH 3 with hydrochloric acid. acidified · The solvent was evaporated and the resulting 1 * 0 g of anhydrous solid was recrystallized from a mixture of ethyl acetate and methanol. 3 * 32 g of 4 - [(2-hydrxx1-3- (2-6) phenyl) - Propyl anino) ethoxy-7-phenylamino-ethyl ester-methyl ester hydrochloride is obtained. op.i 144-146¾.

«Pattra» lines 1 3.-2-3.35 (4d * 2H * CHOMí ^ MlO, 3 * 41 (t * 2H * MtíG ^ cügO) * 3 * 70 (a * 3k * Xüj) * 4 * 06 {d * 2M, OCu ^ CHuM) · 4 * 25 (η, 5H * aHC0 and C ^ Uu), 4 * 72 (β * 2H * OCH ^ CQ) * 6 * 35 (· 18-18 * thienyl), 6 * 74 ( a. 2h * a / lij thienyl) * 6.86-7.02 (a. 4H * CgH ₄ ) · 25 base and £ based on formula · Cyanogenated Ct 51.7 Mi 5.8 Ki 5.4, 7.7 Cl * 8.5>, <

found! Cl 51.8% »Hl 5 * 7 'ό» öi 5.5 λ, ci 7 _t 8 Cli ö _t 7> ·

The starting material is prepared as follows

A mixture of 1.42 g of 2-thienylglyloyl ether, 1.74 g of 4- (2-enino-o-ol) phenol and 60 µl of propen-2-oxo is refluxed for 2 hours. The mixture is packed and the evening dressings are purified by cronetograugation of vg v 60 silica gel · with an increasing amount (8-12 volumes) of unleaded cartalnasal salt as the lysis solvent, mixed with 1.45 g of an oily substance. m.p. 125-127 DEG C., m.p. = 125-127 DEG C., m.p. = 125-127 [deg.] C. m.p. lines 5, υ7 · 5 · 35 (4d, 2M, GHüiiC ^ h), 5.42 (t, 2H, ^ IOIO vügv), 4.08 (d, 2 U _t X ^ gUaOi), 4.21 (t, 28, feHGM ^ CÜQÓ), 4.28 (s, lH, Cjjpíi), 6.55 (a, lH, dq ti.enil * 6.65 -6.88 * (a, 6ií, G ₄ and ₆ u Η, / Hj for thienyl · lozenge spectrum 510 (ΜφΜ) *

W ^ 2 ^ dr ^ l * W 2 -phenyl (2-hydroxy-W 2 * thienyloxy / propyl oaino) -ethyl 7 ' ^: ·, ο> g 4 - ^ - (2-hydroxy-W 2 * thienyloxy / propyl oaino) ethyl From a solution of phenol 7v al dinethoxyl-ethkanul in 0.5 µg potassium arthritis eduiu, the case is stirred for 10 minutes. Ab sufficient crone-acetic acid-net-ester is added and the mixture is stirred for fourteen hours, nojd ai · · · · · · · · · · · · · · · · · volume / wt - female diclar-net containing salt · 7 g of lead

joe stuff down. ··. Dissolve in dichloromethane aq. 8 * solution until acidified with ethereal hydrogencl. solution to give p.i.J., and store the resulting solution. 5 * 4 g of 4- (S) - (2-hydroxy * 3 * (2-thioyl-4'-yl) -propyl-aaino) -? -? - 7 - phenoxyacetate are prepared. ορ · ι 131-13 A.

mm apectma lines 2 * 95-3 * 32 (a * 6H * *

3 * 77 (a * 3 «» x ^) »4 * 11 (d * 2i '., U ^ gMMii) * 4 * 27 (m * 111 * u ^ jusí) * 4 * 31 (s * 2ίϊ * eXMj -vJ) * 6 * 35 (a * l'i * thienil) * 6 * 70 (· & * 2 * 1, H ^ / Kj thienil) * 6 * 92-7 * 50 (a, 411 * νθχΐ ^). .

Ilenséa a Cj ^ lgxMMM.HCl.u *! ίί ^ Ο formula

«/.Shared t Ct 53 * 6 * hl 6 * v f Vol 3 * 5 λ * Five 7 * 9 * * Olt 3 * 5 ·> » HgOl - '* 4 1 found 1 1 53 * 6 add 6 * 1 ... * over 5 * 5 * »* 1 ö * j i * lt o * 5 ··. * J * 1 - · i. baseline; Refer to Figure 2 ^ • 'a-

o * g of 2-thienyl-glycidyl-6 * r * 2 * 0 g of tlxeaine is boiled in 30 ml of propylene-2-oX eu-2 for 2 hours in a stream of water. distil off by pouring into a spit, and xronotogrelate on the OO g & 6C ssili ke gel for volatilization. aethanol tsrtalaesé dichloroacetate

Msanulunk. as an oily substance with a fine chalk weight 0 * 95 Z

4 - {(2-Bioxyloxy-3- (2-thienyloxy) -propyl) -amino} -ethyl} -functional fatty acid 1-6. 'Oh ° c · lines the epectura 2 * dü-2 * 95 (a * 2H *

2 * 95—3 * 25 (a * 4ii * C ^ glviC ^ g) * 4 * 05 (d * 211 * tCj ^ A-Huti) * 4 * 20 (a * lU * Cipii) * 6 * 54 ($ , Ill, thienyl) * Á * 72 (® * 2H, thienyl) *

6 * 75-7 * 10 (a * 4H * C ^).

♦ ·

- 27 TöaegspekfcrtiBi 294 (& * Η) * tlfiOUyii

0 * 6 g of 4- [6- (2-hydroxy-5- (2-thienyloxy) -propylamino) -ethoxy] -phenyl-eoataev-ethyl-ether hydrochloride and 4 ml of 2-azebosethyl A solution of me in methanol (15 µl) was kept in an asobehyde precipitate for 4 hours * The mixture of As was evaporated under reduced pressure (the final traces of its solution were removed by distillation with toluene) * and the resulting 0 * 9 g was distilled over 75 g of K60. dluálósserként 10 ^r v methanol in dichloromethane tertslmoó Aeta hassuálunk * * The resulting oily product 50 dl al chloro chloride was dissolved and a solution PM i 'value from 5 ásványitjuk ethereal hydrogen chloride solution was evaporated oIdáéiért as *, and & alpha aaradékot

The acetate is crystallized from a mixture of methanol and ether * 0 * 55 g of α- (2-ethoxyethyl) -4- [4- (2-hydroxy-5- (2-thlonyl) oxypropylamino) ethoxy] -. phenoxyacetic acid (4'-dichloroacetate) are obtained with a m.p. 145-147 ° C male spectrum at 5 * 07-5 * 50 (a * 11K, and

CligCHgOCH ^) * 4 *> 8 (d * 23 * OC ^ CHCM) * 4 * 20-4 * 58 (a, 5 ^ »éo ⁴ » ⁴⁵ <'» ^2ί1 » °° ^η 2' °) » ⁶ » 54 (η * 111 * M ₅ tiefcil) * 6 * 65 · -6 * 78 (·, 211 * thienil), 6 * 94 (a * 4H * ( ₆ h ₄ ) · ^ leasée e 02 ^^^ * 801 * 0 * 25 HgO formulas underlying ssámitotti 0 · 51% * 6 * 6 * 5 Si>, We * 5 6 6 * 9 n dt _t ι found

C11 7 * 6 S * ^ i 1 * 0

Ct 51 * 4% * Hl 6 * 5 5 ^ * Si 6 * 0 x »* dl 6 * 6 £ - *

011 7 »6% e SgOi o * 5% · * · · · · · ♦ · · ·

- 23 examples

1.6 g of N-tinylglycidyl ether and 3.0 g of N- (2-ethoxyl-4-yl) -4- (2-eninoethoxy) phenoxy-acetic acid are added with 20 ml of propen-2-ol and The solution of ni «etL'Qollel is kept at 4 ° C for 4 hours. distill the solvent and · dissolve the residue on 65 g of £ 60 ozone on a cronetogrel, use 6 volumes of OH as methanol as the cloning agent · yield 2.0 g of ozilOry, l.v. and a solution of ether in ether

acidified to pH 5 with a solution of chlorine · the solvent was evaporated and the residue was crystallized from methanol · 0.7 g of R- (2-non-oxyethyl) -4- [beta] - (2-hydroxy) -1- m.p. = 172-175.5 ° C, m.p. 172-175.5 ° C is obtained in the form of l-oxy (propyl-3-yl) -ethoxy] -T'-phenoxy-ao-ethanol.

Wt spectrum: m / z = 7-3.50 (η, 3H, 0¾½¾ and m ^ gC ^ xa ^), 3.23 (a,> H, 01i ₃ ), 4.01 (η, 2B, Ct ^ CHOH), 4.23 (→ 5H, C ^Ou and C, 4, h6 (e, 2H, OCHCHGO), 6.55 (·, 1B, Bg thienyl), 6.79 (η, 1H, h ₄ tleüli), 6.95 (·, 4B, CgH *), 7.57 (b, 1H, thienyl) ·. lenzés ^{t yl} '20% 3 2 ⁰ 6 · ^Se ® ^Ci ^ 2 ° elapján formula!

dedicated 51.9 '· Ht 6.5 o # Bt 6.1 St 6.9 o, found

BgOt 0.4 a |

Bt 6.3 Rt 5.9 *, o 6.9 ^{S :} ,

HgOl 0.3% ·

The starting material &lt; - &gt; (- (2-aecoxyethyl) -4- (2-eninoethoxy) jtenoxyethylene) is prepared as follows.

3.53 g of N - (2 * netoxyl-ethyl) -4- (2-benzyl) -ethoxy)

-The cetide is dissolved in a mixture of 16 ml of propan-2-ol and 50 nL of methanol, the solution is treated with 1 volume of -O palladium-on-charcoal and the mixture is stirred for 24 hours under an atmosphere of hydrogen gas. ) filter through and evaporate this filtrate to give 3.0 g of K- (2-methoxyethyl) -4- (2-eminoethoxy) * phenoxyethyl ether as an oil, which is used without further purification.

Mass Spectrum ♦ ('B 269 U + H) *

The ash- (2-s-bsil-eniao) -h- (2-s-bsnsil-eniao) time is sequentially eluted as follows: To a suspension of ethoxy1) -phenol in tetrahydrofuran was added 1.2 equivalents of tert-butoxide solution of brine in anhydrous argon under an argon atmosphere. During the addition of the reagent, the mixture was kept at 15-2 ° C and stirred for 1 hour. to the resulting solution was added a solution of 1.1 eq of (S-aethoxyethyl-D-chloroacetenide) in tetrahydrofuran over a period of 15 minutes, stirred for 5 hours, then quenched with approximately an equal volume of water and a rotary evaporator, The aqueous solution was extracted twice with ethyl acetate, and the ethyl acetate extracts were combined and seeded under reduced pressure to give <RTIgt; l- (2-nethoxyethyl) -4- (2-benzylamino) - </RTI> as a solid. Toxic phenoxyetherside was obtained in 90% yield with methyl tert-butyl ether. crystallize from ·

Example 7

A solution of 1.5 M 5-tert-butyl-4-yl-4-tert is 2.75 g in a delayed solution of H.MutylM- (2-enino-ethyl) -phenoxy-cetid in propen-2-ol for 72 hours. kept at room temperature and leptol for scissors * • 50.

yak, and the resulting 4.5 g of rubbery wrw fluff is cleaned with 150 g of K60 color 11 crumbs. The reaction mixture was eluted with methanol / dichloromethane containing methanol-dichloromethane (4-5 volumes). the resulting product (1.4 g) was dissolved in dichloromethane and the solution was acidified to pH 5 with ethereal hydrogen chloride. Evaporate to dissolve As and crystallize the worn gummy material by dissolving it in nethyl-βαβ. the product is recrystallized from methyl ester and methanol. 0.8 g of I *, dimethyl-4- [S] (2-hydroxy-5- [3-thiyl] oxy-propyl-β-amino) -ethyl, 17-renoxy-eaotanide-barium chloride are obtained in a m.p. i25 ^e c <

HAB opectxmm lines 1, υ4 (t, 58,,

1.14 (t, 3Κ → GKj), 2.85-5 »* (m, 10a, * ·, 5.95 (m, 2B, CCCHüü), 4.24 (a, 1H, C COH) .

4.75 (· »2 ', ÜUHgGO), 5.91 (d, 1H, CH-O, $ 6.6 (m, 1H, Hg thienylacetamido), 6, do (m, lu, tlenti B _4), 6.05 * 7.25 (m, 4 ', c ^), 7> 45 (m, 1H, Uenil).

..setting this G ^ aiijjRCy-.ad formula alepian ssámltotti 1 55.8, Ki 6, c ₉ Rí 5.5 & · Olt d, 8 found 1 οι 55 »6 *, Ki 6, o Rt 5.5? Yield 8.8% of starting material B, 13-Ethyl-4- (2-amino-no-tiD-eneoxy-ethamide) as starting material and prepared as follows:

2.44 g of tumorobutoxide are mixed with 150 ml of dimethoxyethane-bound slurry in 4.54 g of N-benzyl-thyrminine. Is the resulting clearing solution 10 suits? After stirring at room temperature, 5.0 g of S _, K-diethylchloro-8cetaldehyde were added and the mixture was stirred for 1 hour. The As mixture was evaporated and the residue dissolved in tanks today was passed through a pad of silica gel. λ filtrate are evaporated, and oily residue is dichloromethane and vis - 51 - bound megossletjuk · «servo solution was separated, szeritjük over magnesium sulphate and evaporated · D-Arg oil boil Center 7 * p & r, i, _{t-diethyl-4-.} (2- / beD8-yl-sino / -ethyl) -methoxyoxyethylene liver. The compound thus obtained was dissolved in 150 * 1 prop-n-2-olbn, to which was added a 10 wt% palladium-on-charcoal space, and the mixture was stirred under an atmosphere of hydrogen for 16 hours. Mixtures of s are filtered through silica gel and the azure windows are inxaxed into 5 · 5 g of Κ, N-diethyl-4- (2-eminoethyl) -renoxyacetate silo as an oil which is used directly without further purification. Example 251 (B * H) * a>

Wg-íiMiUrMi-j- / j-tUnil-MV-oroall-nni.no) —til7-ÍIMri-IHtfH HatmttM

0.15 g tZ? - (2-Hydroyl-5- / 5-thienyloxyl / propyl-only). -Typhenoxyl-ontenrone-ontyl-and -stichloro-HCl 65 ml of anhydrous oxide are added to a solution of 0.3 g of sodium hydroxide in 2 ml, and the mixture is stirred at room temperature for 2 hours. The precipitated crude product is washed with ethanol. Dissolve in 10 ml of water · The aqueous solutions are acidified to pH = 4 by the dropwise addition of 2 l of aqueous saline solution · The solids are solidified · The solid is filtered off and dried over 30 ° C under vacuum at 60 ° C. 4-4 g of? - (2-hydroxy 1-3 / 3-phenyl-ox t i / o -PR propylamine to qualify) eth-f ® 117 * -ecetesvet ^uox was obtained (96% zwitterion 4 · Hydrochloride salt, 0.1 mol crystal water) ορ.ι 170-175®: ·

MW spectral lines 2.83-3, c (2, 2, C ₈ C ₆ Cl ₄ ), 3, ₄ , 5 (40, C 1 H 2 O 4), 5.66-4.04 (d, 2, 1, 10H, CH 2 OH). ), 4.18 (m, 1H, C & OH), 4.56 (β, 2H, OCfigCO), δ> c (a, 1H, Hg tlen III), 6.80 (m, 1H, tlen III), 6, 85-7.25 (m, 4K, c ₆ li ₄ i, 7.4) (β, 1H, 'd ~ becomes; &quot; e ^ * 17 ^ 21') ^V 5 ^ 01 · Q, 1 HgO "t stop) · saéaltotU Hl Ol 57.6 6.0 .., Mn 4.0>, was 9% · vi _f 0 57.7 *> tree was found _was 6.0 ·», Inc. * 3 6 », Wi 9.0

Cl »0.5>» 0t 0.6% S, _with 25 g of 4 l - ^ '- (2-tildx © l -> - / 5-ti.eDÍl Gxi / íM31űo propyl) • heptanoic etoejT -ethacetic acid in a solution of methyl ethyl acetate 100 µl of ethenols added, 33 6 solution of gallic hiriride 3 © 1 in water · The solution was kept for 2 trays for eao skin, shoveled and dissolved in 15 µl of water. · The aqueous solution of 1 aqueous aqueous perchloric acid oleate pH = 5.5 is acidified · The precipitate is washed, deaatylated with water and dried at 60 ° C under vacuum over phosphorus pentoxide · 0.65 g 4- (R) - (2-Hydroxy -> - Z> »theai.l-oxy / * propyl-aeino)« ethex »7« phenoxyaceteave is obtained, m.p. 170-172 °.

? Spectrum calculated: 1-5.5 (··· 6 *, 3? 95-4.05 (?, 2,?, CH 2 Cl 2) 4.2-4.40 (?,? H, C 8 O 10 and? 800¾¾ 0), 4.60 (a, 2H, Od ^ '. O), 6.53 (β, 1H, ¾ thienyl), 6.73 (a, 1H, ii ₄ thienyl), 6.63-6. 93 (n, 4H, C ₆ S _# ), 7.35 (1 H, thienyl).

analysis by formula »calculated» Ο »55» 6 Hl 5 »? 3 » ^a %, more 3.7 M found» Ol 55 »5 Ht 5» 9 Bi 3 * 6%, St 3.7 5 ,.

They £ the RII & .....

Wg-ta-HidMi 1-ί- / 5-ί1 «η11-ωί / _- ΡΓθρί1 - <>» 1Ε3) - «toxiZ = £ aa251 = £ SSHlUdU44UlUfil

-33fiSalt Agar saturated 18C al cold aetsnolhos

1.0 g of 4- [4- (2-hydroxy-5- (3-thienyloxy) -propyl] -oxy] -ethoxy] -phenyl] -ethyl-43 is added. After stirring for 1 hour, the mixture is evaporated to dryness, the residue is dissolved in acetic acid, the ethanol is evaporated to give a colorless solid which is dissolved in a mixture of notanol and dichloroethane and the ethers are diluted with hydrogen chloride solution. Acidify to 5. The solvent was evaporated and the resulting white solid was recrystallized from 120 µL of methanol.

0.61 g of 4- (X- (2-hydroxy-5- (5-thienyloxy) -propylamino) -stoxy) -phenoxyl-ecotanide hydrochloride are charged with m.p. 224-226.

The epithelial lines of H (eq) (W; -Xd ₆ ) t 5.3-5.45 (α, 4 & qysrig) · 5,9-o-4.04 (,, 2M, ^ x ch choh), 4.13-4. , 52 (a, 5 ', cgoa and CH 2 Cl 2 O 3), 4.55 (1, 2H, 1 H), 5.87 ((1H, OH), 6.52 (a, 1H, 1¾ tlenyl), 6.8 (a, 1H, thienyl), 6.86-6.98 (η, 4H, -6¾) · 7.52 U »2H, 00¾), 7.45 (», 1H, thienyl), 9, 05 (a, 2H, 1¾).

iileasés ^C 17®22 ^{M 2U} O5 elapjám

MaBitOttl Cl 50.7 c, Ht 5.7 1 * · 7 »O%, St 8.0% · Clt 8.8 found Cl 50.6%, fit 5» 5, lh 6.9 >>, five 8 , 2%, Clt 8.7.

Examples 11-16 *

The compounds of formula (XIB) listed in Table I · are prepared by the procedure described in Example 1 by isolation of the appropriate mines · λ are isolated in the form of the hydrochloride · the crude product is chromatographed on two 160 columns of silica gel. '' dichloro-net containing methanol ·

....

The example is asaae '7 Op. ° u crystallization solvent aero 11 « CH? 199 * 201 ee taaol / ne t il-eeo tát 12th ^c 2 ^a 5 195 * 196.5 se tenol / se til-ace 13th cyclopropyl 190 * 192 don't teach 14th LBG CSCÜ 171-175 setanol / sekil-eeekát 15th sorfolino 159-161 aeteeol / aekil-eeetát / ether 16th CHgGHeCBg 187-189 not tenol / nekil-aeetat

The epectroscopic analytical data of the compounds obtained are as follows · iU £ »$ ϋΜ

NMR spectral lines 2 * 62-2 * 68 (<* jh * O ^) *

3.0-3 * 45 (a * 4 £ * C ^ NHgGÖg) * 5 * 90-4 * 03 (a, 2B * OQ ^ CHOH) * 4 * 16— -4 * 35 («· 3H * C ^ OM and VHgC ^ O) * 4 * 40 (a * 2H * OCBgCO) * 5 »32-5 * 92 (a * 1H * Ui-O * 6 * 62 (a, 1H * Hg thienyl), 6 * 79 ( η * 1Η »thienyl), 6,8i-7 * vo (a * 4tí * C ₆ K ₄ ), 7 * 44 (a * 1H * thienyl) * 8 * 0 (a * líi * i <iHp * 9 * 07 (a * 2u * 1¾).

fall of 018¾¼¾ ^ö 5 ^f * ^ Ρ ^ ^<6 base ssánitottt Ct 51 * 9 v * Ht 6 * 0 í., Rt 6 * 7 $> * $ t 7 * 7 ft * Olt 8 * 5 M found! Ol 51 * 9% * Hl 5 * 9 X * Ml 6 * 7 X * St'7.7 7, Olt 8 * 7 *.

Talking Spectra> 81 (14 * 8) * á JA »a * lf * mrtM JPW. * Tota« &>

x spectral lines 1 * 1- (t * 3H * CKgCJ ^) * 3 * 13-3 * 52 (a * 6H, qjgWlg and C ^ Cli), 3 * 96-4 * 10 (a * 2H * a HH) , 4 * 22-4 * 38 (·, 38 * C & O and üCSgC ^ O) * 4 * 45 («, 2H, OGiigCu) * 6 * 53 (a * lü *» 2 thienyl) * 6 * 79 (η, IB * H _# tienil) * 6 * 96 (a * 48 * ·· ν ·· «

- 55 CgH ^), 7.35 (b, Ui, tlenyl) ·. • fall from this formula »esáMtotti Ci 33.0 i, Ht 6.3 á, ui 6.5 ..«, δι 7.4 » , Gli 8.5 found »ci 55.1», Hl 6.4 o, H> 6.4% _t 7.6 cli 7.9 χ · Mass Spectrum »395 (M + H) *

The λ5λ £ W & HWlAt h1 spectra are vonslali 0.45-0.74 (a, 4H, CHCl3),?, O (a, 1H, 1 & G &), 5.05-5.48 (a, <♦ 0¾). ^ ¾). 5.95-4.05 (?, 2H,? X ^ H 2 OH), 4.25 (?, 5M, qp? CH 2 Cl 2 O), 4.59 (?, 2H, oh ₂ ?) _T 6.57 (? , 1M, 11% tlenll), €,?> (A, U, ü ₄ tlenll), б, 86-6.90 (a, 4H, 7.59 (a, U * ·, tlenll).

analysis 9 Cg ^^ gHjg, 0jj * j <üGl Formula <l & Pjian Saltwater Gi $ 4.2 ·. ·, xi! 6.1%, i * t 6.3 ^k ·· »^ 9 * ~ cli ö, v λ * found 1 Gi 54.1 Ό, Ht 5.8 <* <6.0 0,. ^ I 7, 5 Clt ö,. ·, »·

T3aag * p * ktzwii * J7 (> '. ♦!:) *

ü. 1 ** IMrtAi l <Ki spectrum lines »2.00 (t, 11, = .CH), 5.1 ^ 5.50 («, 40, C ^ liiiiG ^), 5.95-4.05 U, 4H, CHgCs OCflgCKQB LU), 4.22-4.55 ( «, 3Η» 'U ^Q and H «JfigCggO), 4.48 (β, 2H, OCHgCO), 6.55 (a, 11, Ig thienylacetamido) 6.73 (a, 1H, thienylacetamido), 6.95 (s, 41, C ₄ H, _phenyl),

7.55 (a, 11, 1¾ thienyl) · base salt according to the formula Cg ^^ KgO ^ aSCl (* 0.4 Hg6) »^ sat. Ci 55 * 6 Hl 5.8 St 6.5 1-, 3i 7 , 2%, found!

<11 7.9 HjOi 1.6 M

Cl 55.4, Hl 5.4 Hl 6.2 $, 81 8.4%, vll 8.1 O, HgOi 1.4 '.

U sulfur analysis was performed with a small sample.)

Mass Spectrum »405 (« ♦ !!) *

- J6 a 15. » 1 * 1 ^. IMFlK. the?

3, V-, _5? (? A, chohc? Ku), 3.40-3.68 (?, 1? A,? C? CB? G and a series of? Proton lineages), 5.96-? 4.08 (m, 2H, O ^ gUL d), 4.20-4.57 (· »3 *, C £ OH« WfeCl3feO), 4.75 (9, 2H,), 6.54 <B , 1H, TIG tieuil), 6.78 (*, Ui, thienyl), 6.86-6.97 (s, 4H, C ₆ H _{4) 9} 7.56 ( «, 1H, thienylacetamido).

í.leozéa s ^ 21¾ ^ ¾¾ ⁰ ^ ⁰⁰¹ * 8 ^ ® * »on foot» máfeHatt * Cl $ 53.3, Hl 6.1 · *, five 5.9 1, Bt 6.8 _z i, Olt 7, 5 uli Ci 55.0 ', Hi 6.2. &, five 5.8 4, 3t 6.8 a, clt 7.1!> aogspektiruni 457 (ikh) *

IW1 »1

WH spectrum. Yield: 3.06-5.50 (δ, 4H, cfw), 3.75-3.86 (δ, -28, CfBCB), 5.9-4, δ (a, 2H, G). (G, H, H), 4.18-4.56 (a, 5H, C 8 OH and BCH 2 Cl 2 O), 4.48 (a, 2H, uGdgGO), 5.00-5.18 ((, 2H, G p, 5.71 * 5.93 <»U, c ^ GHg), 6.56 (a, 1H, Hg thienll), 6.78 (b, lii, H _# thienll), 6.96 (e, 4H, C _S H ₄ ), 7.38 (a, 1H, thienyl), tgpigig ^ dgu ^, .HCl

SSáBitOttl VI 54.2 Hl 6.1 ..., Hi 6.5 Z ₉ 4 »7.2 Olt 8.0 S | found 1 ui 54, u .. ·., Hi 5.5 - * ♦ * ·! u, 2.>, 41 7.2, tilt 8.1% <

Yoeespectral 407 (Μί-Η) *

Example 17

1,3 8 4-X- (2H-hydroxy-5- (3H) -yl-propyl-propyl] -beta) -phenol-116 aldialeth, 53 g of potassium -t-butaxide is added and the mixture is refluxed for W minutes. · Evaporate one hundred solvent exchanges,

«. . . «. Dlkot 90 _e K60 ..l _llUíll . _{E te0} « _teeMftlw Hmifcna • 999 ·«

as the stalk, increasing amounts of ueuroyl (6-8 volumes of S) methanol containing methanol / dl-chloro-a / t / ml are used. The worn tear is dissolved in luc zl dl chloromethane in tin and the solution is titrated with ethers hydrochloric acid to pH. Ol and the solvent by dust * »saradékút etonol and propan-2-ol« átkristályősttjük manufactured from, z produce them 6Q 0 ° C. N-monosubstituted Xoofor _t-pentoxide main shaft fired under high vacuum. 0 * 7 g of 2 '- (4-pyridyl-a') III) (2-yl-arc-3- [3-toluene] -1-oxo-1'-opyl-emino) -ethoxyphenylcetaffidide -dlhidroklorld-beaihidrátot kapunké ° i ^<t 12 ^ -131 °? | these fragments are hygroscopic solid.

Spectrum Line 3 * 05-3.46 (a, 4H *

3 * 95-4.05 (a, 2H * 'X ^ gCBöH), 4 * 22-4 * 35 (a, 3ü *. G ^ OB éa 6¾¾ ^ ¾). 4,5Ö <8 * 2H * XHgC),. 4,03 (e * 2fi * CjfeC ^ iO * 6 * 60 (a * Ifi, kong tienll), 6 * 80 (m, Ifi * H * thienyl) * 6. * 99-7 * 03 (η * 4d, C ₆ fi ₄ ), 7.4 (a * Ifi * tienll) * 7.85-8 * 88 (a * 4fi * nleming a 0 ^ ¾Hői. 0 * 5 1 ^ 0 by formula: esanitotti c: 51 * 2% * fii 5 * 7 _{a |} S: 7 * 8 a * ski 5 * 9 ^ *

V 11 13.1 n * BgOi 1.7 f found: C1 51.2% * fi: 5 * 6,. * Ni 7 * 7%. i * 1 6 * 0% · * V 11 12 * 7 figOi 4 * 3 & ·

Example 18

A mixture of 0.63 g of potassium hydroxide * 0 * 68 g of hydroxyeatehydride and 20 ml of methanol is stirred for 30 minutes, to which 0 * 93 g of 4- (2-hydroxy-3- / 3-) is added. tieuil-Ozi / propylamino) ^-etoxj7, i * -phenoxy-acetic ® «methyl-éabp rt <Dutu Ea this suspension was stirred for 6 days. To the mixture was added 3 -1 of vinegar * and stirring was continued for 30 minutes. The winnings won

two of them are filtered off, don't you llel wcsuk, and 110 ol are recrystallized from setenol. u, 42 g of 4- [7- (2-hydroxy-N-tenyloxy-propyl-enino) -to; (~ 7-En-eno-oeto-U-lcarboxyl-dihydrochloride are obtained) m.p. »187-139 °. -λ Ki i-pectime line (hiUO-d 4) »5.00-3.42 (n, 4i, 5.9'0-4.00 (b, 2H, OC 4 -GaOH), 4.15-4 , 5- (b, 5K, <4 uH and CH2 Cl2 X8 H4), 4.38 (β, 2H, ωCH2 CO), 5.05 (d, 1H,

0,6 '(a, Lu, ug dithianyl), 6.78 (b Hl, dithianyl.), 6.9 (in, 4H, - ₆ H _4), 7.42 (®, yl, dithianyl H _§) , 8.9 (s, lil, η £ 0Η), 9 * 05 (e, 2il, K _g ), 10.78 (6, HÍ, ^ 1¾).

alenzée by the formula!

sansitottl Cl 48.8%, Hl 5.5 &, 4 »6.7, -» 7.5 &, vlt ο, 5 | found Ci 48.8 Hi 5.5 o, Hi 0.4., 7.5 ·>, cii 8.8: ..

A mixture of 1.75 g of o-acetylhydroxyl allyl hydrochloride and 1.45 g of potassium hydroxide in 50 ml of netnsolol is stirred at 10 ° C for 10 minutes at room temperature. -tenyl-oxy-1-propyl-a (ina) -e toxyl-phenoxyl-ocetea v-methyl ester was added to the mixture for 14 seconds. The filtrate was evaporated and the filtrates evaporated. The supernatant, 6 grams of asparagus was passed through a short column of silica gel for elution purposes, eluting with 10 volumes of a female cake, Ina salt di chloro-ae. & received 0.5 g & ·. xw.subject from methanol is recycled. · 100 mg of 4- [4- (2-bidroxy-5-chloro-1-oxy] -prop11-®mino) -6 j ox i-aceto-hydroxy-wax-ethyl ester hydrochloride opunkj op. » 162-164¾.

W-spectrum lines 1 5.07-5.46 (a, 4µ, C ^ bik ^), ···:

- 39 Μ5 (· »3Η» 3 »9> 4, υ6 (a, 2d, a ^ CHOH), 4.13-4.32 (a,

JK, QPI houra IDK AGC ^ O), 4 _is 46 (s, 2a, uüHgUO), 6.57 (* »U _t Kg thienyl), 6,7 (10 ski, thienyl H +), was 95 (»» 4ix, C _& H ₄ ), 7.53 (®, 1H, xi ₅ tieuil).

^ len ^ and b C ^ Hg ^ KgO ^ SeHCl form a sheet of Cl 49 »9 0, H 5» 8 0, Si 6.5 Ki 7.4%, cli 3.2? 3a, Hl 5.3 7, p 6.4, St 7.6%, Cli 3.1.

ίν, ι ^ Ζ-α ^ ΐΜ ^ -> ΥΗη »> ατ ^ ί ^»> ν · ° 8ΐΜΐ ·· - * ta.l7-rari ₀ ^ l- ^ c «c« va.tll- * 3zt _a. i · üülltu »

0.63 5 5 potassium tert-butoxide, 1.5 g of {) -4- η 6 - (2-hydroxy-3β-thyloxy) -propylamine-ethyl-4,7-phenol, 10 1 1 dichloro · - methane and 75 L of tetrahydrofuran and stir for 10 minutes.

0.3 g of bromoethyl ether are added and the mixture is stirred for 16 hours. / the steaks are evaporated and the chips are crowned with 30 g <60 aallikagel. · Inhalation volume of mehanoid. Use Ina salt dichloroethane. . o, 62 g of (c) -4 - [(2-Hydroxy-3- / 5-thialoxy] -propyl-eaino) -ExoXT-phenoxylic acid-11-and-hydrochloride kapunké op.i 154-156¾.

The lines of SpAtBrue 3.02-3.45 (α, 4H, C C ^ S / / i ^), 5.7- (δ, 3d · -Uij), 3.92-4.00 (α, 2U, X 1 (CH 2 OH) _t 4.16-4.30 (a, 3H, O 2, and Li 4 GH 2 O 4), 4.74 (a, 2H, OCl 2 C 6), 6.61 (ffl, 1H, 1¾ thienyl), 6.79 (®, 1H, H ₄ tlanil), 6.06 to 6.96 (a, 4H, <y _<4), 7.44 (a, 1H, H ₅ thienyl).

Za7p «-12.5® (, · B, a, uaolDin) · s by s.

· · ·

- 40 satay Οι 51 »7 λ, Hl 9.0, dl 5.4 x, Cl 7,? , CH 3.5 found 'i 51,6 », ui>, 7, οι 1,3 ·>! 7.7 Clá 3 * 4 * .. ·. · Starting material ® is produced in an excellent way

A mixture of 2.1 g of (J-5-thienylglycyl ether, 4.05 g of 4- (2-mlminoethoxy) -yl and 140 ml of prop®n-2-ol was refluxed for 2 hours. The mixture was refluxed and the residue was crude-refluxed on 70 g of KOP-azyl-gel-loaded beaker with ¹ L of UL-UJukal as 6 volumes of methanol in dichloromethane to give 2.7 g of crude product through ethyl * 0 -acetate. 2.4 g of C - [4- (2-hydroxy-3 ', 3-thienyloxy-propyl) -phenyl] -ethoxy] -phenyl] -acetate 139-141.

ωa® spectroscopy 5.04-5.43 (m, 4H,

3.92 * 4.05 (,, 2U, OC ^CHOH), 4.12 * 4.31 (m, 3a, OgKK and hdCHgC ^O), 6.36 (a, III, H ₂ thiooyl), δ , 63 to 6.33 (m, 5H, the _# and * all ti · _C6 fi _4), 7.33 ( «, UI, thienyl).

As U) -3-thienylglycyldiyl &lt; / RTI &gt; was aliquoted as follows: 7 g of (...) - 1- (3-ticnyloxy * propane * 2,3-diol prepared with 100 ml of pyridine, - For a 5 ° o ^ ds boil, 11.0 g of 2-Nephelic »^ salphonyl chloride 01ε is produced in Itsmbea such that ················ · · · · · · · · · · · · · · · · · C. and stirred for 16 hours at 5 ^o C * C * 3 25 * cold solution was' diluted with ethyl ml EOE Tát tel and 50 ®1 kénssv trunks 200 Vissel al;. mégsevényltjuk ktával · l The body layer is separated, and the water is extracted with ethyl acetate, the ethyl acetate-solubilized is clamped, and the product is hepaphorized to give 13.5 g of a gum which is (E) -1- (2-Nophylsulfonyloxy) -5- (3). the ratio of 1-cx1-propon-2-yl and (α-2- (2-naphthyl-8Sulfonyloxyl) -3 → (3-thienyloxy) propen-2-ol 9il, The isomers are separated by chromatography on £ 60 osilix gel with a · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 22 liters of ethyl ether containing cyclohexane as eluent were obtained * as an oily substance, 7 * 5 S (d) -1 • (2-dimethylsulfonyl-oxy) -3 * (3 * thienyl-oxy) -propene. 2 obtains * MMR spectral lines (oocl ^) i 5 * 93-4.02 (a * 2íi, ^ ϊ ^> νΗνΗ) * 4 * 16-4 * 30 (a * 3b * C & OdCl ^ öoOg) · 6 * 13 (»* ili, ili ti— snllí, 6 * 59 (a * U * h ₄ thienyl) * 7 * 10 (» * líi, tlenU), 7,56-0 * 53 (® * 7h, a mixedlsthea The chemical shift of tri-chloroacetate 1-iaocienate ®dvs e proton occurs at 5 * 35 pgm, indicating that the ssulXonate group is bound by the ε-proxy bidroxyl group *

5 * 5 g of a solution of (u) -1- (2-methylsulphonyloxy) -> (3-thienyl * asyl) -propan-2-ol in 20 ml of dimethyl-uulphOMide delayed * 1 * 5 S sodium hydroxide The mixture was stirred for 15 minutes * quenched with 50 ml * and quenched with 4 * 2 ml of ethyl acetate. The extracts were combined and dried over anhydrous sulfide * and evaporated. ) -3-thienylglycidyl ether was obtained as an oil.

mi spectrum lines (orol ^) i 2 * 63-2 * 94 (a * 211 * .jjgOUii) * 3 * 26—3 * 3h (a, 1 * 1 * Cd) * 3 * 81 · —4.25 ( m, ccj ^ wii ^ íl) *

6.30 (a * 12, hg thienyl) * 6.7 «(a * lu, d ^ thienyl), 7.1Ö (a * Ui, Hj thienyl).

As (u) -1- (3 »tleDIL-axif-propa-2,3-dol) is the following • · · ·;

·· ··. ....

·· * ··. * · ·

- We produce it in 42 ways

92.4 g (, 3 - (-) - 2, 3: 1-tert-1,3-dioxola-4-ethenol,

A mixture of 1.5 liters of di®: tert-butyl-ethane and 78.4 g of Aliantexobutoxide was stirred until the weight of the δ potassium salt was dissolved in argon-staphosphere · 0.63 g of potassium iodide, 28 g of copper oxide and 65 »13 3-bromothiophene were added and the mixture was stirred for up to 10 people at 90 ° C. The reaction mixture was cooled, diluted with 200 µl ether, and the inorganic salts were removed by filtration. - The beer slurry was evaporated under high pressure to give 131 g of allyl, b.me.

235 g of * .G- silica gel were purified by chromatography on 4 volumes of ethyl acetate using dichloromethane as eluant. - taste: image of propylidene-propane-2,5-did 41 g of this material

Dissolve 250 [mu] l in 80 [deg.] C., 00 [deg.] C. and immerse the solution in a boiling water bath for 40 minutes. The reagent was evaporated and the reagent was removed by distillation of the last hyoaol in toluene to obtain a residue (55 g) which crystallized out from ethyl acetate. 22.5 8 (µ) -1- (3-toluene-1-oxo) -propan-2, - diol fcspunkf 0; ..: 71-73®C * ϊίΚτ spakur lines. ®ιϊι 2 * 0 (s, llí * OH),

2.55 (s, Ι, 3), 3.72-3.85 (a, 2H,.% 3H), 4.04-4.11 (a, JH, X 1 H 2 Cl 2 OH), 6.30 (a). , 1H, thienyl H _2), 6.77 (a, IH, H _# thienyl), 7.19 (a, III, H ₅ thienyl).

The compound (it) - (-) - 2.2 ,. -trtfluoro-1- (9-entril) -etcholine 'dv® 9 lines would not separate ·

-mino) «« toxi7 - ^ «nozl-« c «t» aid «lsaiitAa»

1 »25 8 (S) - * .X - (2-Hydroxy-5- (5-thienyloxy) propyl · · ·

- 43-enin)) »tMxj / -yloxyacetate ^ v-ethyl-and» ver 100 al methanol cbtwdkig 50 al 33 -oc eunoloe se 111 * · «min solubilized solution * ..the solution at 24 crushed with saoU-beetroot * we cracked κ rengine na for solubility in cheese · the resulting 1 * 1 g sexe sachet was dissolved in dichloromethane and uethanol * and the solution was ether with ethereal xi-chloride solution * Acidify to 3 · The solvent is evaporated off * methanol is added to the residue * and methanol is evaporated again. The resulting 1 * 3 S product of 40 ml of methanol was oxidized to dryness. * 1 * v2 g of (.) -: - i-Ethyl-4-42 '- (2-hydroxy-oxy ->-> - thienyloxy-propyl). 1-asino) -e toxjZ- ^ ® ^ûVX * · * · ^c ®nid-Hydroclox id> t topunk | op.t 200-201¾ * «-12 * 6 ° (c» v * 5> - * in matsnol) · spectral lines (Dsayay-d ^) i 2 * 66 (d * 3 -E * 3 * 90-3, 45 (tt * 48 * C ^ KHCgg), 3.94-4,> (d. 2u, <X ^ CO). 4 * 18-4 * 36 (tt * 38 * C & pU and CHgCygu) * 4 * 41 (a * au * OGH ^ oO) * 5 * 90 (d * 18, CUG &) * 6.64 (m * Ili, ^ 2 thienyl) * 6.80 (η * 1H * H ₄ thienyl) * 6 * oe (s * 48, c _fe H ₄ ) * 7 * 46 u. Il, thienyl) * 8 * 03 (a. 1H * Ι ^ ΟΙ ^) * 9 * 1 (e * 18, ..il) »fisamén á ^ 8 ^ 4¾¾ ^ * ' ^ic ^ formula elepjan ssánitottt Ci> 1,9 ··., Iís 6 * 0 * out 6 * 7> * 8i 7,7 í * Cli 8 * 5 | found! C l> 1 * 6 /. * ni 6 * v »* j $ i 6 * 6> * Sí 7 * 5 ^ - '* cl! 3 * 4 »/.'· & 2a ..... aáXM

UdA ^ ÍMltfat ^^ ArHtBU ^ V. ^ aÍBBUclÍMlMl-aitr 'alZtftmte'fiUffM tWUUUM

To 1.5 liters of saturated cold methanol, saturated with 32 g of () -4- [4- (t-hydroxy-3- / 3-la-n-oxy) -px-o-yl] -aino] n-cis-acetic acid-octyl ester is added · Stirring is carried out for 4 hours * The solvent and reagent are evaporated (to remove the reagent by distillation of the fragments ® and ®) · The brewing medium 1 * Dissolve in a mixture of 5 liters of illicit methanol and 1 liter of dichloromethane * and dilute with ethereal hydrogen chloride solution

- Yeast 44 pH * 5. the mixture is concentrated and the crude area of the topped g is crystallized from 4 liters of satonol ·

27.8. g of C4-4- [beta] - (2-hydroxy-3- / 3-thienyl-axiyl-propyl- (3-amino) -boxo-7-phenoxy] -cetomide hydrochloride is obtained, m.p. defined by) apectron lines of 3.05 to 5.50 (η, 4H,

3.95-4.00 (a, 2, OC2CH2OH), 4.16-4,> 4 (a, 3 ', C & OH &lt; V &gt;), 4.40 (a, 2H, XHgCO), 6 61 (a, 1 H, Hg thienyl), 6.82 (a, _t 2K thienyl ₄ H), 6.97 (e, 4u, 0 ₆ H _4), 7.44 (a, 10, ylmethylcarbamoyloxy) .Uesaés based on the top of Ο ^^^ Ο ^, pl!

eeuuitotti Cl 5 ->, 8 bars 5.5 Hi ?, £, ^ i 8.0 ·, cli 8.8 .4 satel VI 50.7 i, Hi 5.5 W, 1 * · 6.8, · .! 3.1>, li 3.8 ·

Torne gspektruni + ϊΑδ 567 (^ * 0) *

Λ7ξ ⁵ «-14.0® (β» in 0.1 methanol) · 2¾. EXAMPLE u, g g-3-thienylglycidyl ether, 1 g g 2- (2-otoxyethoxy) -Xenl47-ethylene-ene (the disclosed European Patent Application 254 856 is the property of &amp; bebeu). and 25 ml of prepan-2-ol are boiled under reflux for 5 peoples. and methanol and acidified to pH = 3 with ethereal hydrogen chloride solution. The solvent is evaporated off and the sera is mixed with 25 ml of ethyl acetate and a few steps of methanol. recrystallized * 0.105 g of 3- [4- (2-oxo-1-oxy-1-ynyl) -amino] -7- (5-tolyloxy) -propene. 2-ol hydrochloride was added ορ · ι Χ66-168 ° 0 · h'S Spectral lines: 1.15 (t, JH, CH ₂ q ^), 2.33-3.01 (», 2H, C ^ C _€ H ₄ ), 3.01 -5.27 «, 4H, (^ ^ W · 3 * 44-3.50 (q, 2H, C ^CHj), 3.64-3.75 (pr <, 2H, OC OCCHgO), 5.9-4.02 (a, 21i * ^ 0¾), 4.02-4.1 (pr, d, 2fi, XHgCf10), 4.13-4.27 (, Ifi, qpi), 6.53 (η * 1H, Hg thienyl), 6.7 ^ (*, 13, H _# thienyl), 6.35 • 7.25 (». 4H, c ₆ li ₄ ), 7.40 (a, 1H, B ^ tUnil).

Killed by 8 Cj ^ Hj ^ SÜ ^ .i.HGI formula!

esaturated Cl 56.3 S, Hl 7.0 &gt; R 5.5 5.5 9 3.0 3.0 <tb> Sat ci 57.1, Hl 6.5 v, N: 3.5, t 3.1.

B ·, .aíU &

(I) 4- / 5- (a-üidro »i-I- / I-ti" Nil o «V Bropil- ^ amino) -

4.55 g of 4- [beta] - (2-hydroxy-3 · 5-thiol 1 · ·χ1 / · ρΓορ11-β-ηηο)--ethoxyl-phenoxy-ether-methyl-ester, 4.6 g (- ) -di-p-tQlaeil tartaric acid is concentrated in a mixture of 40 volumes of netanol to about 10 volumes of oxalate in a final volume of 50 volumes of ethyl acetate / dana and concentrated to a volume of 25 volumes. Leave to stand for> 2 hours at room temperature for 13 hours. The precipitated exile material was removed by evaporation and recrystallized from methanol * 3.1 g of (h) -4- [4- (2-hydroxy-5- / 5-thienyl-oxy-propyl) -ol] ) ^-etoxj7> -INOX ecet8sv-ro-methyl-register é - ( «) - receives a hydrogen-di-p-toluoyl-terbarátot« nk? | ορ · ι 145-147¾, · * 78 * 3® (c * 1.1, needle in females) * pseudonym for formula sham 1 Cl 59.5 «» Hl 5 * 5 & · R 1 * 3 £, 31 4,2 * <found! ci 59.5> ** fii 5.6 λ: 1.3. , kills 4.2? ·

5 * 0 g of (S) -4 - [(2-Hydroxy-1- [3- (3-trifluoromethyl) -propyl-ethyl] -one] texXT'-phenoxyl-acetic acid &lt; / RTI > - (-) - Hydrogen-dl-p-toluoyl tartrate is separated by a 5% w / v solution of sodium hydrogencarbonate and 1 hg of chloroform · 1 hg * dried over kagnesia sulfate and the solvent was evaporated. The solid cores were crystallized from methanol. 1 * 4 g of (µ) -4- [4- (2 * hydroxy * 5 - (-) - thienyloxy] -propylamino) -ethoxy] -phenoxy-aoe-toluene methyl ester cake. | m.p. 94-96 ° C * XV ^ «* 5® (o = 0 * 99 in methanol) ·. * 81 8 * 4 | found · Gi $ 6 * 7><^; t ül 50 ^ i 5 »7 · * © i 8 * 5 '>' ♦

0 * 175 6 (O) -4- [N- (2-Hydroxy-5- (5-thienyloxy) propyl] amino] -ethyl-17-phenoxyacetylmethyl-ether> ml of ethyl * acetate, saturated ethereal auxiliary chloride solution was added and the mixture was heated. the precipitated solid was recrystallized from methanol and acetyl acetate · 162 g of (v) -4-? - (2-hydroxy-5- (5-toluene) 11-oxo-propylsmino). - · t oxy 7 -phenoxyethem. v-ma-ethyl ester hydrochloride op ·· 154-155 ° C * »-11 * 5 ° (©« 0 * 97 .. »in methanol) · analysis & formula« page · shifted · wi y. * 7 o * beat 5 * 7> · 5 * 4 a> * cu 8 * 5 st 7 * 7 found · Gi 51 * 7 M · 5 * 5% * «5» 2 * · Cl * 8 * 4 0 * 01 7 * 6 Í5a ihíáVg l ^ «>.« r- (2 ^ drail-3- / Í-tÍ «tiU.-oxl / -oronll -«. inüy-ttcxl7-ln _Q xl- « _C .t» «« eialltaA ».

1 * g of () -4- ££ - (2-td.dxo-Al-5 - [*] thienyloxy / propylamino) -ethoxy _] -phenoxyacetylcavmethyl * and 3ter * 20 ml methanol * 1 * 25 ml of water and 0 * 125 g of sodium hydroxide were kept at room temperature for 5 hours · the solvent was evaporated * the solid residue

- I bless in 47 * distilled water, and the ρϋ of solution s is stated to be 5.25 * ro, the solid which is precipitated is separated and soeeuk. 0.82 g of (.4-4,4,4,4,4-hydroxy-3 * / 3 * thienyloxy-propylanino) -ethyl17 * phenoxy-acetea ** bGnihydrate is obtained. up = 176-177 ° C, -6.6 ° (e = 1.0%, in dinethylsulfoxia) · .beta. 9a, Ski>, 7R, Ski 8.5%,

HgOl 2.4% | found Cl 54.2%, Ml 6.0 r ₉ Al 3 * 8 8.6 s, iixjUi <i, 6 '«·

Ether saturated with a solution of 0.175 g of (.;) -? 4 -? - (2-hydroxy-? Hydrochloric acid solution was added and the mixture was incinerated. Then a first 60 ml of ether was added. 3- (5-Thienyloxy-propyl-snylo) -ethyl] -7-phenoxy-ethyl acetate hydrochloride is obtained. ορ · ι 172®C, £ *%? $? · * 12.4® (e «1.01 &, Eetenolbao) ·

Rlesmés C ^^ Hg | LiO _6; Based> IICL formula asánitotti * Ct> u, 6%, 5 Hl "5 5.5", Cl ci * 8.3 * 7 * 9 Ί found ol 50.6. a, Mi 5.2%, Mi 5 * 5 cl * 8.7 S, 8 »8.0» ·

26 · example

0.2 g of 4-4? - (2-hydroxy-3 - [(3-thioyl) -oxy-propyl] -no-nno) -ethoxy] -7-xenoxy-acetic acid * notyl-ester, 5 -13-eneino- keep prop @ nl-ol at boiling water for 3 times · A; The mixture was cooled, treated with 5 ml of ethyl acetate and then quenched with saturated hydrogen chloride solution. solvent solvent excess

- 4 leg g of water are distilled off under reduced pressure · the aliquot is added to 5 vi of water and the mixture is heated. The oily precipitate is filtered off with suction and crystallized from ethyl acetate / ethyl acetate / 12 g of methoxypropyl 4-ethyl (2-hydroxy-5). - oxy / propyl-aaino-e toxj7 * C enoxy-ec «teaide hydrochloride gates op · * 172-174 ° U.

'Breathing on this page of the CggHggögOgbUiCi formula * aeaaalot Cl 52 * 1, ~ * Hi 6 * 5 a * R * 6 * 1 A, 1 * 7 * 7 over 7 «O | * * y2, l * * ixi 6.2. > Ml 6 * v ** Olt 7 * 4 .- », rl / * 1 - '* · 27 · example

UvArvtMWti Bal-mi HlblHU · as lanterns are prepared by the treatment of tertalnasal salt with the help of oameral oenological operations. rain pharmaceutically * tilag sl & i ^ züatG salts (e.g., sharp examples compounds ser int produced) hasznaiőuk tel · the tablet of ttswtlen compression "ALTI prepared * falls ⁸ excipient to wet granulation * the gramilútuahos aikronisált and / falls to ground Ick Toit and isaert disintegrating agent and the blend is blended * and this mixture is compressed.

Claims (15)

1 »Compounds of Formula (I) and Medicine Scars Scalable Salts - 9 Formulas X represents a ton of oxygen or ve, a hydrogen bond and a chlorine atom containing a propane-halogenated chain and a fluoroethane represented by a carboxyl group, (1-6 exenatoe alkoxylcarboxyl group 1-6). <w bleaches - <t <h ² h ^ or - (vH _? ) _e or ^ generic copy group, as in the latter formulas 1 < ² hydrogen * toaot, optionally n-hydroxyl, 1-4 s-alkenoxyalkoxy, phenoxy *, rb4o11-, (1-6 sennoalkyl) alkylcarbaoyl, d1- (C 1-6 alkyl) 1-6 eaenepheoaoe elicyl or 5-6 arenyl elenyl, substituted by carboxyl, pyridyl, phentyl, chlorophenyl, chloro-pyridyl, 3-6 benzene-elenyl, 3-6 aryl-cyclo-1- or optionally halogen, 1-4 carbon atoms alkyl, 1-4 alkenoxy alkoxy, trifluoromethyl, cyano, or nitro-esubstituents on the backbone denotes phenyl radicals, and at the same time denotes? hydrogen is a tooth, 1-6 carbon atoms or an alkyl radical of the formula -CS ⁴ , and R ⁴ is hydrogen, optionally hydroxyl C 1-6 alkyl substituted with 1-4 C 1-6 C 1-6 alkoxy, preferably 3-C 6 alkenyl substituted with C 1-4 alkoxy substituted with hydroxyl, 3 * 6 C-alkenylM * ··· · - 50 powders, phenylcarbonate, n-naphthyl, phenyl * (I * 4-ethenethyl group) or BSftil * (C 1 -C 4 -alkyl), or h ² and together form a 4- to 7-membered polystylene chain, where one of the methylene groups may be optionally substituted with at least two random nitrogen atoms in the oxygen atom, and the two adjacent carbons of the polyethylene chain may be optionally part of a benzene ring condensed with a poly (methylene chain) and - (1-4C) alkyl, C 1-4 -alkoxy, trifluoromethyl, cisno * or nitro-substituents, or it may be ² and ²⁴ together to form a 3-4 membered polyethylene chain, represents a hydrogen atom, a C 1-4 alkylene group or a C 1-4 alkanoyl group and n represents 1, 3 or 5 * The compounds of formula (I) according to claim 2 &lt; 1 &gt; * and the most useful salts thereof in which thienyloxy-propyl-amino-ethyl or thienyloxy-propyl-anino * -ethoxy-substituent and as-éριΙ ^ α ¹ osubaztituena are paraffin-related relative to each other · 3 «Compounds of general formula (I) according to claim 1 or 2« and pharmaceutically acceptable salts thereof * wherein H ° is hydrogen. A compound of the general formula (I) as claimed in any one of claims 1-3 and pharmaceutically acceptable salts thereof. means oxygen atom · 5 · alphabetic (1) according to any one of claims 1 * 4 · - The compounds of formula 51 and their pharmaceutically acceptable salts in the formula «z-oxyl-propyl-amino-ol-ll ~ are attached to the 5th position of the thiophene ring. A compound of formula (XI) and a pharmaceutically acceptable salt thereof, wherein X is an oxygen atom or a bond, and Η ^{δ is} kerboxyl *, (1-6 carbon atoms) - carbonyl 1-, carbamoyl, (1-6 alkylene) carboxyl, hydroxy- (1-6 carbonene-containing 81kiD-carbamol 1-, (1 * 4 carbon atom &lt; c &gt;)) - ( 1 * 6 alkyl (alkyl) «xrbemoyl, di- (1-6 alkylene) alkyl, piperidine, one moiety moiety · 7 · (Compounds of formula IixJ and their pharmaceutically acceptable salts - wherein carboxyl, aethoxycarbonyl, xrbamoyl, methylcarbamoyl or (2-methoxyethyl) -carbamoyl) are represented by · 8 * as 1 * 7 · Optically active modifiers of any of the foregoing compounds 9 · 4-4? (2-Hydroxy-5 ~ / 5-tienyloxy / * propylamino) * * · ti ^ T ^ eno a i-ece tea v- «e 111-éa x tar, 4-4? - (2-Hydroxy-5- (5-thienyloxy-propyl-1-one) * tac-7 * phenoxy-acetic tea-methyl, ( _? ) -4 * 4- (2-Hydroxy-5- [5- (5-thienyl) oxy] propyl] -ethyl] anoxyacetate-ethyl-ester, and (R) -4-4- (2-) bidroxy-5 - [(-) - thienyl-OA (propyl enino) -e tox] 7 * -phenoxy-aca tsa v-t1-1 and x vol. 1G · 4-4? * (2-HidX'Ox 1 * 5 * / 5-le nyl-oxy / propyl-ool) -? -? -? - F -Thoxyoxy-acetic acid, 4 * ^ 5- (2 * hydroxy-5- / 5-nyl * oxy / * pro pi 1-a) c) 1117 * 1anoxy -etaetaev, (O) (2-hydroxy-1- (N-thienyl) -propyl-enino) -ethoxy-17-phenyloxy-acetic acid, and (α) -4- [4- (2-hydroxy-3-) »Thienyloxy / propyl-eBino) -otl47 ^> « <phenoxy-ether · 11? - (2-ethoxyethyl) -4- [4- (2-hydroxy-N- (5-thienyl) propylsino] ethoxy] phenoxyacetamide; iwae ti-N-N-Ca-hydroxy-N, N-thienyloxy-4-propyl-eBinol-ethoxy-4-phenoxy-acetic acid, 4- [4- (2-Hydroxy -? - (-) - thionyl-oxy-propyl-amino) -ethyl] -7-phenoxy-ethyl, (S) -4- _[ 5- (a-hydroxy-3) - (5-thiaryloxy) -propyl- (amino) -ethoxy7 ^, " ^phen " oxy-tea, 5-ethyl-tert-F- (2-hydroxy-3 - [[beta] -N-oxy-2-propyl-eaino) -e toxo] -N-oxy-eco-endaldehyde, and (SM) ~ 1-4- ^ 5 - (2-Hi-oxy-3- / 3-methyl-1-oxy / propyl-enlno) -e tox17-phenoxy-ee teas · 12 · medical preparation, eagle 1 1 e a e 1v e that it is 1-11 · claim tertalaas healing of the stakes according to the requirements of the points together with barrel, dilution and other auxiliary agents · Method 1 <RTI ID = 0.0> * 1 </RTI> of the compound of the formula (I) eseriati (X) and pharmaceutically suitable for the preparation of a medicament, wherein a) Compounds of formula 0 (III) * wherein h ° and v are as defined in claim 1 «singly - reacting with compound pump (arc) alt * lanooe - in which formula ¹ is as defined in claim 1 and - ® © port means - | or • · · · · ·······························································• - 53 · bi as (Vt) - · where fi is as defined in claim 1 - - in which ee R ¹ is as defined in claim 1 - or c) reducing the compounds of the general formula (Vx1) - in the formula a, k® and bs 1 · - obsession d) -Λ is hydrolyzed to produce the compounds of formula (I) of the general formula &lt; RTI ID = 0.0 &gt;&lt; / RTI &gt; and (1) in the abstracted case, you _; therein, compounds of general formula (1) are converted to salts of compounds of formula (X), and compounds of formula (1) are converted into their pharmaceutically acceptable salts. · Compounds of formula (JU) - in which Π ® hydrogen represents an chloro or fluorinated female * and x represents a valence or oxygen relative to the eco or aminopropoxy solanilane moiety · · Compounds of formula (vili) - wherein the hydrogen on the toe or the ratio on the eu-propoxy-solution is in the ortho or 4 «position of the linked chlorofluoride and represents λ valence or oxygen · 16 · C4-5-lieoyl-glycyl ether · Characterized in that the compounds of formula (1) or the pharmaceutically acceptable salts thereof are prepared according to claim 13, wherein M ¹ and X are present 54 · · 4 · · · · · · · · · · · · · · · · · · · · Glues as defined in Claim 1 - the usual diluent for medical use, and the use of other materials for the treatment of medicinal products. skate kit. for the applicant, the aeghatalaeiotti